The objective of this proposal is to explore the factors that have contributed to the observed geographic co-clustering in bladder cancer mortality and arsenic concentrations in drinking water in Michigan. The focus will be on the spatial and spatio-temporal patterns of arsenic exposure and how these may relate to the incidence of bladder cancer in those areas of Michigan with elevated levels of arsenic in their drinking water. Reported arsenic concentrations in well waters in the study area range from 1 to 1310 mg/I, with most common levels being 5-50 mg/L. The project being proposed will consist of three components: (1) Construction of exposure scenarios with time dimension that will involve development of the novel space-time information system (STIS) model to be validated using a combination of space-and-time-dependent concentrations of arsenic measured in the study, supplementary historical information on arsenic levels in water supplies, hydrogeochemistry of the area, and self-reported residence information and water drinking habits; (2) Biomonitoring of arsenic exposure to be based on analysis of toenails (known to indicate average exposure over a relatively long time) for arsenic and a number of confounding trace elements such as selenium, zinc, copper and antimony; (3) A population-based, case-control bladder cancer study which will be used as an outcome measure for exposure to arsenic in drinking water. Bladder cancer cases (700) and controls (700, matched to cases by sex, race, and +/- 5-year age groups) will be recruited from long-term residents of the 11 counties (Genesee, Huron, lngham, Jackson, Lapeer, Livingston, Oakland, Sanilac, Shiawassee, Tuscola and Washtenaw) with elevated levels of arsenic in their groundwater. Structured personal interviews will be administered to obtain information on lifetime residential history, current and past water consumption patterns, life-style risk factors (including cigarette smoking and alcohol use), medical history, occupational history, family history of cancer, and dietary habits. The study is designed to shed some light on the dose-response relations for exposure of the U.S. population to arsenic concentrations in the 5-100 mg/L range where no information currently exists. Current efforts by the U.S. Environmental Protection Agency to reduce the maximum contaminant level for arsenic in our drinking water have been bedeviled by contradictory and unvalidated predictions of the risks of chronic exposure to low levels (< 100 mg/L) of arsenic in water.